PROJECT 2: Project Summary/Abstract Frontotemporal lobar dementia (FTLD) is the second most common cause of dementia in people over 65 years of age. In a subset of FTLD cases, aggregated tau is the major neuropathological feature (FTLD-Tau). FTLD- Tau includes progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which are the focus of this project. In both disorders, aggregated tau is found in both neurons and glial cells. PSP and CBD belong to a larger group of neurodegenerative diseases called tauopathies, disorders with aggregated tau as part of the neuropathologic signature of each disease. The most common tauopathy that has the largest economic, medical, and personal costs is Alzheimer's disease (AD). All tauopathies are presently essentially untreatable. The goal of this project is to deconstruct the genetic and genomic architecture of tauopathies with a focus on PSP and CBD. The rationale for the project is to: 1) Predict who will develop tauopathies. When prevention therapies become available, genetics will contribute to predicting who should be treated and when. 2) Understand tauopathy pathogenesis. Gene discovery can identify pathways not presently implicated in these disorders. Pathways potentially involved in FTLD-Tau include all aspects of tau spreading including initial aggregate formation, release form cells, uptake by adjacent cells, release in to the cytoplasm, formation of seeded aggregates, and response to either a toxic tau-related entity, or response to tau depletion. 3) Identify therapeutic targets. Genetic studies leading to gene discovery are essential for finding new therapeutic targets. We will use a multi-pronged approach to tauopathy genetics. We will: 1) Identify genes where loss- of-function variants prevent tauopathies (protective genes) using a C. elegans tauopathy model; 2) Identify novel PSP and CBD causative/risk genes using whole exome sequence analysis to identify causative variants. Genes identified in both phases will then be tested in both C. elegans and mammalian tauopathy models; 3) identify causative variants in MAPT region regulatory elements that affect expression of MAPT and other nearby genes. This work has the potential to identify therapeutic targets for not only PSP and CBD, but also to AD, the most prevalent tauopathy.